The present invention relates to ceftiofur, its intermediate and preparation of ceftiofur. This invention relates to a new method of preparation of syn 7-[2-(amino-1,3-thiazol-4-yl)-2-(methoxyimino)acetamido]-3-[2-furylcar bonylthiomethyl]-3-cephem-4-carboxylic acid, also known as ceftiofur, of the formula 
which is a cephalosporin antibiotic useful in treating bovine respiratory disease.
1. Field of the Invention
This invention describes the preparation of ceftiofur starting from 7-amino-3-(2-furylcarbonylthiomethyl)-3-cephem-4-carboxylic acid, hereafter called as Furaca of the formula 
through an open side chain route where the formation of the thiazolyl ring of ceftiofur is achieved in the final step.
2. Description of the Related Art
U.S. Pat. No. 4,464,367 by Labeeuw teaches a process of preparation of ceftiofur. Ceftiofur was synthesized by condensing activated syn isomer of (2-tritylamino-4-thiazolyl)-2-methoxyimino acetic acid of the formula 
with Furaca in presence of triethylamine to yield tritylceftiofur which on further treatment with aqueous formic acid yielded ceftiofur.
U.S. Pat. No. 5,583,216 by Takeda Chemical Industries Ltd. teaches a process to prepare cephem compounds and claims an acylation whereby (2-amino-4-thiazolyl)-2-methoxyiminoacetyl group is introduced on the 7-amino group of a cephem moiety.
It is well known in the literature that the thiazole ring formation as a final step has been used for the preparation of cephalosporin antibiotics but there are no reports yet to date for the preparation of Ceftiofur by such a methodology. It is probable that no one to date has developed such a route and that the yields are either generally considered low and have failed to be reported. U.S. Pat. Nos. 4,458,072 and 4,482,710 are included here as reference.
The present invention provides a novel method of preparation of ceftiofur in high yield from Furaca comprising of the following steps:
(a) condensation of 4-bromo-2-methoxyimino-3-oxobutyryl chloride with silylated Furaca
(b) the isolation of the resulting product
7-[4-Bromo-2-methoxyimino-3-oxobutyramido]-3-[2-furylcarb onylthiomethyl]-3-cephem-4-carboxylic acid of the formula 
xe2x80x83in pure form and referred to as the bromo intermediate
(c) Cyclization of the bromo intermediate to yield ceftiofur